ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.3988+2T>C

gnomAD frequency: 0.00001  dbSNP: rs745349258
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001953915 SCV002239104 pathogenic not provided 2022-12-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1457730). This variant is also known as c.3991+2T>C. Disruption of this splice site has been observed in individuals with ABCC8-related conditions (PMID: 27188453, 33046911). This variant is present in population databases (rs745349258, gnomAD 0.002%). This sequence change affects a donor splice site in intron 32 of the ABCC8 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003321888 SCV004026519 pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2023-08-16 criteria provided, single submitter curation The c.3988+2T>C variant in ABCC8 has been reported in 2 individuals with hyperinsulinemic hypoglycemia (PMID: 27188453), segregated with disease in 2 affected relatives from 2 families, and has been identified in 0.002% (2/113628) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs745349258). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1457730) and has been interpreted as pathogenic by Invitae. Of the 4 affected individuals, 1 of those was a homozygote, which increases the likelihood that the c.3988+2T>C variant is pathogenic (PMID: 27188453). This variant is located in the 5' splice region. Computational tools do predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PM2_supporting, PP1 (Richards 2015).
Baylor Genetics RCV003471186 SCV004199698 pathogenic Type 2 diabetes mellitus 2023-06-30 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005042602 SCV005681074 likely pathogenic Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3 2024-06-10 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.